With the advent of new biotechnology methods and recombinant technologies, many new and potent biotherapeutics are being synthesized. Pharmaceutical scientists are posed with the challenge of developing novel drug delivery systems to effectively deliver these molecules to sites of action. These new delivery systems must be capable of overcoming biochemical and anatomic barriers to aid drug transport, control the rate and duration of drug release, prevent the macromolecules from enzymatic or in situ degradation, and deliver the drug to the target site.
Oral drug delivery has been the most successful to date in delivering conventional drugs. These new biotherapeutics however, are susceptible to degradation in the harsh acidic and enzymatic environment of the gastrointestinal tract and first pass metabolism in the liver leading to low bioavailability.
In comparison, hypodermic injections are a more effective drug delivery system, since drugs delivered by intravenous injections bypass first pass metabolism. However, hypodermic injections have their own limitations. These include pain, risk of infection, need of trained personnel for drug administration as well as requirements for sharps disposal.
As a result of these limitations, a more effective drug delivery method is sought after with little or none of the limitations of the hypodermic needles or by oral delivery routes. Transdermal drug delivery has evolved to have a significant impact in the drug delivery horizon and is competing to provide a viable alternative to oral delivery and hypodermic injection. Delivering a drug through this route offers several advantages such as the avoidance of premature metabolism of drugs in gut and liver leading to dose sparing and is less painful than hypodermic injections which generate dangerous biomedical waste and pose the risk of transmission of disease if the needles are reused. Transdermal systems are non-invasive and are amenable to self administration, thus increasing patient compliance and reducing medical costs.
Transdermal delivery systems include topical formulations and more recently, transdermal patches. Topical formulations such as gels, ointments and creams have been used for decades now and have been successful for local and short term treatment with small, lipophilic and low-dose drugs. Transdermal patches have been approved for sale for lipophilic drugs such as scopolamine, nicotine, fentanyl as well as estradiol and have been widely used for a variety of conditions. Each year more than 1 billion transdermal patches are being manufactured and a new patch has been approved every 7.5 months between 2003-2007.
Despite being advantageous in a variety of conditions, these transdermal drug delivery systems have not been adapted for novel biotherapeutics such as proteins, peptide and vaccines. These new compounds cannot cross the biological barrier of stratum corneum at therapeutically useful rates due to their hydrophilicity and large molecular weights. The outermost layer of epidermis, the stratum corneum is 10-15 μm thick and prevents molecules larger than 400 Da to passively diffuse to the subcutaneous tissues. This is exemplified by the fact that the smallest drug currently manufactured in a patch is nicotine (162 Da) and the largest is oxybutynin (359 Da). Creating delivery systems to deliver these big molecules has been a major challenge to formulation scientists in the past decade.
To deliver these big molecules, an array of methods has been researched, including chemical penetration enhancers, iontophoresis, ultrasound, laser and electroporation. Numerous chemical excipients in pharmaceutical formulations that disrupt the bilayer structures of stratum corneum have been studied for their permeation enhancing effects. The major drawback with these chemical agents is the accompanied skin irritation, which correlates with increased permeation. Iontophoresis, which primarily depends upon an electrical force driving the charged molecules across the stratum corneum, has also been limited in application for large molecules due to limited ability to disrupt the skin barrier. It has been thus used for molecules weighing only a few thousand Daltons. Ultrasound, which is an oscillating pressure wave, has been thought to increase skin permeability by generating pressure gradients and oscillations that drive the drug molecules into the skin. Like iontophoresis, ultrasound has also been able to increase the permeability of small lipophilic drug molecules. Electroporation uses short, high voltage pulses to disrupt lipid bilayers of stratum corneum aiding the diffusion of lipophilic as well as hydrophilic drugs. However, the associated pain due to high electric field and the resulting muscle stimulation is an area of concern and the technique has not been widely researched due to complex requirements of the device setup. Although all these methods are conceptually sound, none of them has been able to make a convincing impact in delivering high molecular weight and hydrophilic molecules across the stratum corneum.
Recently, high precision microelectronic tools and miniaturization techniques, first adapted in the semiconductor industry, have been tailored to design micron scale drug delivery systems such as microneedles. Microneedles are small micron scale devices consisting of numerous projections, where the height and shape of such projections are governed by the fabrication process. Microneedles are applied to the skin in a manner similar to the transdermal patch, and create pores in micron scale range in the stratum corneum, thereby allowing the passage of hydrophilic as well as large molecular weight drugs through the skin and mimicking aspects of hypodermic needles. Microneedles can therefore be considered to be a hybrid drug delivery system between the safe and convenient transdermal patch and efficient hypodermic injections.
Since microneedles are in the micron scale (600-700 microns long, 10-60 micron tip diameter), they do not penetrate deep enough into the skin to stimulate pain receptors and hence are relatively pain free. Trauma to the application site is also low due to the small size of microneedles, and hence wound healing is relatively fast. It has also been shown that transient pores created by microneedles close within 72 hours after removal of the microneedles. This makes the use of microneedles very appealing to patients with impaired healing or requiring frequent injections such as diabetic patients. Lastly, microneedles do not require specialized training for use.
A drug moiety can either be coated on the microneedles or encapsulated in their core and delivered to the subcutaneous tissues. The microneedles are expected to evade any nerve fibers or blood vessels that reside in the dermal layer due to their small size, and this has been clinically proven in a previous study.
Many research groups have extensively studied and used various materials and fabrication techniques. Microneedles have been fabricated from silicon, metals, zeolite and polymers. The widespread use of silicon in the microelectronics industry and its relatively low cost made it a suitable material for microneedle fabrication in the early stages of development of microneedles.
Polymeric microneedles have received much attention from the drug delivery scientists in the recent years with several methods being developed to fabricate microneedles from polymers. Various polymers including poly (vinyl pyrrolidone), its co-polymer with methacrylic acid and poly-lactide-co-glycolide have been used. Sugars and sugar derivatives like dextrose, maltose, galactose, carboxymethylcellulose and amylopectin have also been used for fabricating microneedles. These materials used are biocompatible, cost effective and generate no biohazardous waste.
Drugs have been delivered by either coating on to the shafts of the silicon or metallic microneedles. However, with this approach, only a limited amount of drug could be loaded on to the microneedle shafts, curtailing significant drug dosage. Another approach involved pre-treating the skin with microneedles to create transient pores and drugs were applied in the form of drug solutions. The brittle nature of silicon and metallic microneedle is a serious concern. These materials are not biodegradable and their biocompatibility is questionable, involving the risk of if they break in the skin or are inadvertently misused. On the other hand, polymeric microneedles have been used encapsulate the drugs in addition to drug coating and pre-treatment of skin with their predecessors. Most of these previously developed polymeric microneedles focused on protein drugs such as insulin, heparin and vaccines. They have been shown release the load when inserted in to the skin. The drugs released from the microneedles can form a depot from where they can be absorbed to systemic circulation or lymphatic vessels. Encapsulation of drugs within the polymeric core offers the advantage of higher drug loading and the convenience of formulation omitting multiple steps. Hence encapsulation of drugs within the microneedles has received most attention from the transdermal drug delivery scientists in the past 2-3 years. However the fabrication approaches used for these microneedles were harsh, and cannot be generalized to ensure the stability of proteins. High temperatures (150-160° C.) have been used for micromolding of sugar microneedles, whereas long exposures to ultraviolet light have been used for microneedles developed from poly (vinylpyrrolidone). Casting methods used by other groups utilize polymers or sugar derivatives requiring the concentration of hydrogel using high temperature and vacuum which have been shown their deleterious effects on the fragile protein molecules. Other complex procedures like wet silicon etching, reactive ion etching and laser based methods involve elaborate processing which accrue the overall cost of the process.